Metabolic adaption of macrophages to heme detoxification in systemic vascular inflammation

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SUMMARY Hemolysis accompanies many pathologies including trauma, sepsis, hemorrhagic stroke, malaria, and genetic disorders such as sickle cell disease (SCD) and glucose-6-phosphate dehydrogenase (G6PD) deficiency. The release of free heme into the circulation promotes numerous vascular pathologies and therefore, efficient heme clearance and detoxification is necessary to prevent sustained tissue damage. Chronic hemolysis results in vascular inflammation driven by free heme, accompanied by oxidative tissue damage, which may lead to generation of oxidized phospholipids that are implicated in atherosclerosis and cardiometabolic disease complications. Here, we will test the overall hypothesis that in settings of hemolytic stress, G6PD deficiency becomes increasingly detrimental due to dysfunctional metabolic adaptation, and that metabolic adaptation of macrophages and monocytes is essential for the resolution of hemorrhage in SCD. In specific aim 1 we will test the hypothesis that metabolic adaptation in macrophages is necessary for efficient heme-clearance and cell survival and to determine the molecular mechanisms that regulate the metabolic shift to the PPP in the context of hemolysis. We will also examine the consequences of insufficient heme detoxification for cell survival and lipid oxidation in systemic hemolysis in G6PD and Steap3 transgenic mice and test the hypothesis that the phosphofructokinase PBFKB3 is the target for CO to activate the PPP. In specific aim 2 we will demonstrate the significance of metabolic adaptation to heme detoxification in SCD. We will examine metabolic shift in murine models of SCD and characterize blood monocyte metabolic state in SCD patients. These studies will identify novel therapeutic targets to improve heme detoxification and ameliorate heme-induced oxidative tissue damage.